1. Field of the Invention
This invention relates generally to field of immunology and specifically to human monoclonal antibodies which bind and neutralize Herpes simplex virus (HSV) Type-1 and Type-2.
2. Description of Related Art
Herpes simplex virus (HSV) remains one of the most common viral maladies in man, achieving a worldwide distribution and causing a variety of infections. Two forms of the virus, HSV Type-1 (HSV-1) and HSV Type-2 (HSV-2), have been distinguished by clinical, biochemical, and serological criteria. HSV-2 is more commonly implicated in genital infection, while HSV-1 is associated with oral and ocular disease. Both types of the virus may become latent after traveling intranasally to sensory ganglia.
Primary and secondary herpes infections in individuals immunocompromised by underlying disease or immunosupressive drugs are often more severe than in the normal host. Such individuals, which include AIDS patients, those with hematological or lymphoreticular neoplasms, (Siegal, et al., N. Engl. J. Med., 305:1439-1444, 1981; Greenberg, et al., J. Infect. Dis., 156:280-287, 1987; Buss, et al., J.A.M.A., 243:1903-1905, 1980) and organ and bone marrow transplant recipients, are also prone to increased frequency of secondary herpes episodes. In the case of transplant recipients, the severity of herpes infection correlates with the degree of immunosuppressive therapy employed (Rand, et al., N. Engl. J. Med., 296:1372-1377, 1977).
Devastating illness may also result from HSV infection of the neonate. In the U.S., such infections are encountered in 1 in 2,500 to 1 in 5,000 deliveries per year, most being acquired following intrapartum contact with infected genital secretions (Whitley, Virology eds., 2nd Eds:1843-1889, 1990). As compared to a recurrent episode, primary infection occurring late in pregnancy generally produces more frequent and severe disease in the newborn. This correlates with a greater maternal viral load at delivery (Corey, et al., Ann. Intem. Med., 98:958-972, 1983), probably arising because the immune reponse to the virus is only in its early stages.
Current therapy of herpes infections is limited, although acyclovir, vidarabine and related drugs have proven useful for the management of specific infections such as mucocutaneous herpes infections in the immunocompromised host, herpes simplex encephalitis and neonatal herpes. Recurrent episodes, however, are less responsive. Moreover, viral strains resistant to these drugs have been isolated from immunocompromised patients (Englund, et al., Ann. Int. Med., 112:416-422, 1990; Sacks, et al., supra; Erlich, et al., N. Engl. J. Med., 320:293-296, 1989). A potential alternative approcah to HSV prevention and therapy is offered by specific human antibodies to the virus. Such reagents, if highly efficient in virus neutralization and in mediating the clearance of virally infected cells, may prove useful in replacing or complementing existing clinical regimes.
There is evidence of a significant protective role for antibody in human infection in vivo. The presence of neutralizing antibody in acute phase serum during primary infections has been associated with reduced severity and duration of the primarly genital herpes episode (Core, J.A.M.A., 248:1041-1049, 1982). Further, it has been shown that the development of recurrent genital herpes in an individual following a primary infection with homologous virus is inversely correlated with the titer of HSV-2 neutralizing antibody in the convalescent serum (Reeves, et al., N. Engl. J. Med., 305:315-319, 1981). Moreover, the titer of anti-HSV antibodies in bone marrow transplant recipients is predictive of the risk of infection (Pass, et al., J. Infect. Dis., 140:487-491, 1979). In vitro, human serum antibody has additionally been shown to neutralize extra-cellular virus and lyse certain HSV-infected cells (Allison, Transplant Ref., 19:3-55, 1974).
HSV is a complex virus. Over 50 virus encoded polypeptides, including both structural (envelope and core) and regulatory proteins, have been identified in infected cells. Analysis of the humoral response against HSV and the identification and characterization of potentially protective antigens has been undertaken largely using human sera and mouse monoclonal antibodies (Fujinaga, et al., J. Infect. Dis., 155:45-53, 1987; Kapoor, et al., J. Gen. Virol., 60:225-233, 1982; Kumel, et al., J. Virol., 56:930-937, 1985; Rector, et al., J. Fen. Virol., 65:657-661, 1984; Simmons, et al., J. Virol., 53:944-948, 1985; Kuhn, et al., J. Med. Virol., 23:135-150, 1987). The main targets of the humoral and cellular responses appear to be the 7 well characterized HSV envelope glycoproteins, gB, gC, gD, gE, gG, gH and gl, which are found both on the virion and on the infected cell surface where they are thought to promote viral attachment and penetration through multiple interactions between themselves and the cell membrane. Only gB, gD and gH have been found to be indispensable for viral growth in cell culture. Virus mutants defective in these molecules will bind to the host cell surface, but are unable to penetrate into the cytoplasm (Desai, et al., J. Gen. Virol., 69:1147-1156, 1988; Fuller, et al., J. Virol., 63:3435-3443, 1989; Ugas, et al., J. Virol., 62:1486-1494, 1988; Weber, et al., Science, 236:576579, 1987). Those glycoproteins which are mandatory for virus attachment have not yet been identified.
Each envelope glycoprotein is capable of eliciting mouse monoclonal antibodies able to neutralize virus in vitro (Whitley, et al., Virology eds., 2nd Ed:1843-1889, 1990). Passive immunization with monoclonal antibodies specific for gB, gC, gD, gE and gH has also been shown to protect animals from infection (Kumel, et al., J. Virol., 56:930-937, 1985; Simmons, et al., J. Virol., 53:944-948, 1985; Balachandran, et al., Infect. Immun., 37:1132-1137, 1982; Dix, et al., Infect Immun., 34:192-199, 1981). In addition, polyclonal immune sera and gD specific monoclonal antibodies have been shown to protect mice from recurrent disease (Simmons, et al., J. Virol., 53:944-948, 1985). It has also been demonstrated that monoclonal antibodies against gB and gE suppress the replication of HSV-1 in trigeminal ganglia (Oakes, et al., J. Virol., 51:656-661, 1984). Glycoproteins B and D appear to elicit a major part of the antibody response to virus in humans and also appear to be the major targets of neutralizing antibodies (Kuhn, et al., J. Med. Virol., 23:135-150, 1987).
There is thus a considerable body of evidence illustrating the potential value of monoclonal antibodies as agents for immune prophylaxis and therapy in HSV infection. The development of combinatorial antibody libraries displayed on the surface of phage offers the possibility of accessing monoclonal human antibody specificities against infectious agents from any individual with clearly demonstrable serum antibodies against the pathogen (Williamson, et al., Proc. Nat'l Acad. Sci. USA, 90:4141-4145, 1993). In the present invention, a library from a long term asymptomatic HIV-1 positive individual with serum antibody titer against HSV-1 and HSV-2 was used to isolate a diverse array of human monoclonal antibodies specific for these two viruses. The generation of panels of antibodies using this methodology permits a thorough characterization of the human antibody response to these pathogens and further identify particular antibodies of potential value for clinical applications. The present invention provides such an HSV neutralizing human antibody.